Tryptophan depletion in depressed patients occurs independent of kynurenine pathway activation

Brain Behav Immun. 2012 Aug;26(6):979-87. doi: 10.1016/j.bbi.2012.05.010. Epub 2012 Jun 6.


The kynurenine pathway (KP) and its rate-limiting tryptophan degrading enzyme indolamine 2,3-dioxygenase (IDO) have been implicated in the pathogenesis of depression. IDO expression is driven by inflammatory cytokines, and has been suggested as the link between inflammation and a serotonergic deficit in depression. Studies also indicate that inflammatory cytokines upregulate the serotonin transporter (SERT), representing another mechanism by which inflammation could influence serotonin availability. Here we examined circulating concentrations of inflammatory cytokines (IFN-γ, TNF-α, IL-1β, IL-6), and the acute phase protein CRP alongside plasma tryptophan, kynurenine, kynurenic acid (KYNA) and 3-hydroxyanthranilic acid (3-HAA) concentrations, and whole blood mRNA expression of IDO, kynurenine aminotransferases (KAT I and II), kynurenine-3-monooxygenase (KMO), kynureninase and SERT in patients with major depressive disorder (MDD) compared with age and sex-matched controls. Whilst no changes in TNF-α or IL-1β were observed, plasma concentrations of IL-6, IFN-γ and CRP were increased in the depressed cohort. Despite this inflammatory phenotype, IDO expression or plasma kynurenine were not significantly different between MDD patients and controls. In addition, there was no difference between controls and depressives in concentrations of KYNA and 3-HAA, or in expression of enzymes KAT, KMO or kynureninase that drive their production. Nonetheless, a depletion in tryptophan was evident in depressed patients and was correlated with HAM-D scores. In addition, we failed to observe any difference in SERT mRNA expression in the blood cells from patients with MDD relative to controls. These data support the idea that a mild inflammatory signature is evident in MDD and is accompanied by reduced circulating tryptophan concentrations. However, we found no indication of KP activation in the depressed cohort suggesting that an alternative mechanism mediates the depletion of tryptophan observed. Taken together these data question the ability of the mild inflammatory phenotype observed in depression to induce molecules such as IDO and SERT that could negatively impact upon serotonergic functioning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers / analysis
  • C-Reactive Protein / analysis
  • C-Reactive Protein / metabolism
  • Chromatography, High Pressure Liquid
  • Cytokines / blood
  • Depressive Disorder, Major / metabolism*
  • Female
  • Humans
  • Kynurenine / blood
  • Kynurenine / physiology*
  • Male
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Signal Transduction / physiology*
  • Tryptophan / blood
  • Tryptophan / deficiency*


  • Biomarkers
  • Cytokines
  • RNA, Messenger
  • Serotonin Plasma Membrane Transport Proteins
  • Kynurenine
  • Tryptophan
  • C-Reactive Protein